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John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop

John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop John Fossella, PhD Sackler Institute. Tool #1: Genome Sequence Databases. The Human Genome Project. TIGR: 1 microbe per day: Sargasso Sea. Tool #2: Human Genome Variation Databases.

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John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop

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  1. John Merck Fund Summer Institute on the Biology of Developmental Disabilities Genetics Workshop John Fossella, PhD Sackler Institute

  2. Tool #1: Genome Sequence Databases The Human Genome Project TIGR: 1 microbe per day: Sargasso Sea

  3. Tool #2: Human Genome Variation Databases Patient Group Control Group ….AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTACACACACCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAGACCACAGATTGACC ATGATCGCAGTCGCAGATCTCT CTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCT CGGCTTAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT……. ….AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTTCATAGATCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAGACCACAGATTGACC ATGATCGCAGTCGCTAATCTCT CTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCT CGGCATAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT…….

  4. Tool #3: Genetic Origins of Psychopathology Neuregulin –Schizophrenia RGS4 -Schizophrenia Neuroligin -Autism 5HTT -Anxiety, Depression Calcineurin -Schizophrenia DYX1C1 –Reading disorder DRD4 –ADHD FMRP -Fragile X MAOA –Aggression GPR56 -Frontal cortex structure

  5. Tool #4: Brain Gene Expression Databases

  6. Tool #5: Mouse Models of Brain Development and Behavior “The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain” Zhao et al. (2003) PNAS 100 (15) pp. 9005-9010

  7. The Scientist Volume 17, June 2003 Whole-Genome SNP Genotyping Four highly parallel approaches make the technically intractable a reality Tool #6: High Throughput Genotyping

  8. Hariri et al., (2002) Science

  9. There are many issues to consider When designing a behavioral or imaging-genetics study: What phenotype(s) ? a chance to integrate multiple levels of analysis Population Structure & Study design ? families, volunteers & patients What genetic markers or candidate genes ? biological pathways Genotyping technology cost & convenience Statistical analysis and reporting of data statistical nightmare, biology can light the way A few grant writing and IRB issues 

  10. Goal of the Genetics Workshop: Impart an understanding of: The molecular nature of DNA Of the structure of a gene & genome Of variation in the genome Of the historical origins of variation How 1-5 are used in the design of studies

  11. The molecular structure of DNA

  12. How many bases ? How many genes ? How many variable sites ?

  13. Goal of the Genetics Workshop: Impart an understanding of: The molecular nature of DNA Of the structure of a gene & genome Of variation in the genome Of the historical origins of variation How 1-5 are used in the design of studies

  14. What is a gene ? The Central Dogma

  15. Goal of the Genetics Workshop: Impart an understanding of: The molecular nature of DNA Of the structure of a gene & genome Of variation in the genome Of the historical origins of variation How 1-5 are used in the design of studies

  16. 3 million polymorphic sites Single Nucleotide Polymorphisms (SNPs) …AGTTCGATTGCTCGATAGCACGAT… …AGTTCAATTGCTTGATAGCACGAT… …AGTTCGATTGCTTGATAGCTCGAT… Repeats …AGTTCAATTGCTTGATAGCGCGAT… …AGTTCAATTGCTTGCTTGCTTGATAGCGCGAT… Deletions …AGTTCAATTGATAGCGCGAT…

  17. Protein Structure Polymorphisms Polymorphisms in the DRD4 gene

  18. Glu CB1, BDNF D2short DRD4 mGlu MAOA DA MAOA DA facilitates NMDA and Ca++ influx (permits weight change) COMT

  19. DA Receptor G-protein Beta-arrestin

  20. Protein Structure Valine / Methionine Polymorphisms in the COMT gene

  21. Gene Regulation Polymorphisms 5HTT “long” allele lower 5HT 5HTT “short” allele higher 5HT Why are carriers of the 5HTT “short” allele more susceptible to affective disorders ?

  22. Goal of the Genetics Workshop: Impart an understanding of: The molecular nature of DNA Of the structure of a gene & genome Of variation in the genome Of the historical origins of variation How 1-5 are used in the design of studies

  23. 3 million polymorphic sites Single Nucleotide Polymorphisms (SNPs) …AGTTCGATTGCTCGATAGCACGAT… …AGTTCAATTGCTTGATAGCACGAT… …AGTTCGATTGCTTGATAGCTCGAT… Repeats …AGTTCAATTGCTTGATAGCGCGAT… …AGTTCAATTGCTTGCTTGCTTGATAGCGCGAT… Deletions …AGTTCAATTGATAGCGCGAT…

  24. DNA Replication “Mistakes”

  25. Human GTGATGAC Bonobo GTGCTGAC Chimpanzee GTGCTGAC Gorilla GTGCTGAT Orangutan ATGCTGAT C to A change T to C change A to G change The collection of “mistakes” is an history book of evolution

  26. “Mitochondrial Eve” & Y-chromosomal Adam

  27.   

  28.   

  29. Goal of the Genetics Workshop: Impart an understanding of: The molecular nature of DNA Of the structure of a gene & genome Of variation in the genome Of the historical origins of variation How 1-5 are used in the design of studies

  30. Efficient Executive Attention Group Poor Executive Attention Group ….AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTACACACACCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAGACCACAGATTGACC ATGATCGCAGTCGCAGATCTCT CTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCT CGGCTTAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT……. ….AGTGTTCGATAGCTGTTGAC ATGATCGCTGTCGCTAATCTCG CTTCATAGATCACAGAATGACA ATGATCGCTGTCGCTAATCTCT TTTCATAGACCACAGATTGACC ATGATCGCAGTCGCTAATCTCT CTTCATAGAGCACAGATCGACT ATGATCGCTGTCTCTAATCTCT TTCACATAGATCGAGATGGACA ATGATCGCTGAAGCTAATCTCT CGGCATAGATCACAGATTGACA GTGATCGCTGTTGCTAATCTCT CTACCATAGATCACAGACTGAA GATCGCTCGATAGAAGAT……. How do we know that the yellow T influences variation in executive attention ?

  31. Pedigree, family-based design “T”

  32. Case-control design: Qualitative trait 5% “T” 60% “T” Efficient Executive Attention Group Poor Executive Attention Group

  33. Case-control design: Qualitative trait 5% “T” 60% “T” Efficient Executive Attention Group Poor Executive Attention Group

  34. Case-control design: Qualitative trait 5% “T” 60% “T” Efficient Chopstick Dexterity Group Poor Chopstick Dexterity Group

  35. Asian Non-asian Case-control design: Quantitative trait Allele “T” Allele 1 Attentional Efficiency

  36. Asian Non-asian Case-control design: Quantitative trait Allele “T” Allele 1 Dexterity with chopsticks

  37. (rare) between group vs. (abundant) within group variation

  38. There are many issues to consider When designing a behavioral or imaging-genetics study: What phenotype(s) ? a chance to integrate multiple levels of analysis Population Structure & Study design ? twins, families, volunteers & patients What genetic markers or candidate genes ? biological pathways Genotyping technology cost & convenience Statistical analysis and reporting of data statistical nightmare, biology can light the way A few grant writing and IRB issues 

  39. Roche Genetics Education Online Course http://www.roche.com/home/science/sci_gengen/sci_gengen_cdrom/sci_gengen_cdrom_online.htm National Genographic’s Genographic Project https://www5.nationalgeographic.com/genographic/atlas.html

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